This is a revised application for the competitive renewal of our productive investigations with respect to """"""""Childhood Metabolic Markers of Adult Morbidity in Blacks"""""""", HD27503-09. Blacks are at increased risk for obesity, type 2 diabetes mellitus and cardiovascular disease. A common pathogenetic link among these entities is insulin resistance/hyperinsulinemia. During the previous project period, our results demonstrated that: 1) black children have lower insulin sensitivity and higher insulin secretion compared with their white peers. However, the insulin hypersecretion in blacks is over and above the compensatory response to lower insulin sensitivity. 2) Rates of total body lipolysis are 40% lower in black vs white children. 3) In situations where there is a demand to increase ?-cell insulin secretion, black children have a limited capacity to do so. Based on these findings we propose the following theory: decreased lipolysis in black children leads to 1) accumulation of fat in skeletal muscle responsible for the insulin resistance, and 2) accumulation of fat in the ?-cell responsible for the insulin hypersecretion initially. This hyperinsulinemia further augments tissue fat trapping. With time, in the presence of excess energy intake and/or diminished physical activity, insulin resistance intensifies and ?-cell """"""""lipotoxicity"""""""" renders the islets incapable of further increases in insulin secretion to match insulin resistance.
The specific aims of this competitive renewal are: 1) to compare skeletal muscle lipid content (SMLC) in black vs white children by computed tomography (CT) scan of the mid-thigh, and assess the relationship to in vivo insulin sensitivity; 2) to test the hypothesis that free fatty acid (FFA) -induced insulin resistance is associated with larger increases in SMLC in black vs white adolescents; 3) to examine if ?-cell insulin secretion in prepubertal black children is more sensitive to the stimulatory effect of FFA than in whites; and 4) to test if the ?-cell in black obese adolescents is more susceptible to the lipotoxic effect of FFA compared with whites. The methods to be used are: the well-established CT method to assess SMLC; intralipid infusion to elevate circulating FFA levels; the hyperinsulinemiceuglycemic clamp with stable isotopes and indirect calorimetry to measure insulin sensitivity and substrate turnover; the hyperglycemic clamp to assess insulin secretion; DEXA and abdominal CT for body composition assessments. A comprehensive understanding of the mechanism(s) of racial differences in insulin resistance/hyperinsulinemia is important in targeting specific therapies to the metabolic tissue(s) involved. The ultimate goal is to reduce the morbidity and mortality related to obesity, T2DM and CVD in black Americans by intervention/prevention strategies early in childhood. ? ? ?
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